Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma
- Heather Francis1,2,3,4,
- Sharon DeMorrow1,2,3,
- Julie Venter3,
- Paolo Onori5,
- Mellanie White3,
- Eugenio Gaudio6,
- Taylor Francis4,
- John F Greene Jr7,
- Steve Tran4,
- Cynthia J Meininger8,
- Gianfranco Alpini1,2,3
- 1Division of Research, Central Texas Veterans Health Care System, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
- 2Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
- 3Department of Medicine, Division of Gastroenterology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
- 4Division of Research and Education, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
- 5Department of Experimental Medicine, State University of L'Aquila, Italy
- 6Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of the Studies of La Sapienza, Rome, Italy
- 7Department of Pathology, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
- 8Department of Systems Biology and Translational Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, USA
- Correspondence to Dr Gianfranco Alpini, Scott & White Digestive Diseases Research Center, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Olin E Teague Medical Center, 1901 South 1st Street, Bldg 205, 1R60, Temple, TX 76504, USA;
Contributors HF: overseeing the research project with GA, writing of manuscript and performed all the molecular studies. SDeM: helped with paper writing and molecular studies. JV: cell culture and transfections. PO: some of the immunohistochemical data and paper writing. MW: real-time PCR and some of the immunohistochemical data. EG: some of the immunohistochemical data and paper writing. TF: real-time PCR and immunoblots. JJG Jr: assisted with paper writing and discussions on project. ST: immunoblots. CJM: assisted with paper writing and discussions on project. GA: overseeing the research project.
- Revised 28 June 2011
- Accepted 1 July 2011
- Published Online First 26 August 2011
Background In several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1–H4 histamine receptors (HRs).
Objective To determine the effects of histamine stimulation and inhibition of histamine synthesis (by modulation of HDC) on cholangiocarcinoma growth.
Methods In vitro studies were performed using multiple human cholangiocarcinoma lines. The expression levels of the histamine synthetic machinery and HRs were evaluated along with the effects of histamine stimulation and inhibition on cholangiocarcinoma proliferation. A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC. Vascular endothelial growth factor (VEGF) expression was measured in cholangiocarcinoma cells concomitant with the evaluation of the expression of CD31 in endothelial cells in the tumour microenvironment.
Results Cholangiocarcinoma cells display (1) enhanced HDC and decreased monoamine oxidase B expression resulting in increased histamine secretion; and (2) increased expression of H1–H4 HRs. Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells. Long-term treatment with histamine increased proliferation and VEGF expression in cholangiocarcinoma that was blocked by HDC inhibitor and the H1HR antagonist. In nude mice, histamine increased tumour growth (up to 25%) and VEGF expression whereas inhibition of histamine synthesis (by reduction of HDC) ablated the autocrine stimulation of histamine on tumour growth (∼80%) and VEGF expression. No changes in angiogenesis (evaluated by changes in CD31 immunoreactivity) were detected in the in vivo treatment groups.
Conclusion The novel concept that an autocrine loop (consisting of enhanced histamine synthesis by HDC) sustains cholangiocarcinoma growth is proposed. Drug targeting of HDC may be important for treatment of patients with cholangiocarcinoma.
- biliary cancer
- biliary physiology
- biliary epithelium
- molecular biology
- bile acid
- cell signalling
- biliary secretion
- cell cycle
- liver regeneration
- Helicobacter pylori
- acid-related diseases
- non-ulcer dyspepsia
- genetic polymorphisms
- gastric neoplasia
- colorectal cancer genes
- microsatellite instability
- cell cycle
- gastrointestinal neoplasia
- molecular pathology
- pathobiology of biliary epithelia
- biliary epithelium
Funding This work was supported by the Dr Nicholas C Hightower Centennial Chair of Gastroenterology from Scott & White, a VA Research Career Scientist Award, a VA Merit award and NIH grants DK58411 and DK76898 to GA and Federate Athenaeum funds from University of Rome “La Sapienza” to EG. This work was partially funded by a Scott & White Mentored Research Grant awarded to HF.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.